title: Tyrosine kinase inhibitors are potent acute pulmonary vasodilators in rats.
abstract: Tyrosine kinase inhibitors are promising for the treatment of severe pulmonary hypertension. Their therapeutic effects are postulated to be due to inhibition of cell growth-related kinases and attenuation of vascular remodeling. Their potential vasodilatory activities have not been explored. Vasorelaxant effects of the tyrosine kinase inhibitors imatinib, sorafenib, and nilotinib were examined in isolated pulmonary arterial rings from normal and pulmonary hypertensive rats. Phosphorylation of myosin light chain phosphatase and myosin light chain was assessed by Western blots. Acute hemodynamic effects of imatinib were tested in the pulmonary hypertensive rats. In normal pulmonary arteries, imatinib reversed serotonin- and U46619-induced contractions in a concentration-dependent and endothelium-independent manner. Sorafenib and nilotinib relaxed U46619-induced contraction. Imatinib inhibited activation of myosin phosphatase induced by U46619 in normal pulmonary arteries. All three tyrosine kinase inhibitors concentration-dependently and completely reversed the spontaneous contraction of hypertensive pulmonary arterial rings unmasked by inhibition of nitric oxide synthase. Acute intravenous administration of imatinib reduced high right ventricular systolic pressure in pulmonary hypertensive rats, with little effect on left ventricular systolic pressure and cardiac output. We conclude that tyrosine kinase inhibitors have potent pulmonary vasodilatory activity, which could contribute to their long-term beneficial effect against pulmonary hypertension. Vascular smooth muscle relaxation mediated via activation of myosin light chain phosphatase (Ca(2+) desensitization) appears to play a role in the imatinib-induced pulmonary vasodilation.
authors.affiliation: Department of Pharmacology, University of South Alabama, Mobile, Alabama, USA.
authors.forename: Kohtaro
authors.initials: K
authors.lastname: Abe
authors.forename: Michie
authors.initials: M
authors.lastname: Toba
authors.forename: Abdallah
authors.initials: A
authors.lastname: Alzoubi
authors.forename: Karel
authors.initials: K
authors.lastname: Koubsky
authors.forename: Masako
authors.initials: M
authors.lastname: Ito
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ota
authors.forename: Salina
authors.initials: S
authors.lastname: Gairhe
authors.forename: William T
authors.initials: WT
authors.lastname: Gerthoffer
authors.forename: Karen A
authors.initials: KA
authors.lastname: Fagan
authors.forename: Ivan F
authors.initials: IF
authors.lastname: McMurtry
authors.forename: Masahiko
authors.initials: M
authors.lastname: Oka
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001549:Benzamides; D001557:Benzenesulfonates / Q000494:pharmacology; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D000068877:Imatinib Mesylate; D008297:Male; D018994:Myosin Light Chains / Q000378:metabolism; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects* / Q000503:physiopathology; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077157:Sorafenib; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects; D016278:Ventricular Function, Right / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D001549:Benzamides; D001557:Benzenesulfonates; D018994:Myosin Light Chains; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D014665:Vasodilator Agents; D009536:Niacinamide; D000068877:Imatinib Mesylate; D000077157:Sorafenib; D011505:Protein-Tyrosine Kinases; D043263:Myosin-Light-Chain Phosphatase; C498826:nilotinib; D002118:Calcium